1、ASTROBIOLOGY SCIENCE CONFERENCE 2006Washington,DCMarch 25 31,2006Viral Evolution03.29.06HEPATITIS B VIRUS:COMMENTS ON VIRAL AND HUMAN EVOLUTIONBaruch S.BlumbergFox Chase Cancer CenterPhiladelphia,PA,19111,USA1.Hepatitis B Virus is a very common virus.2.Humans have been infected with virus for a very
2、 long time,possibly from the time of the origin of humans.3.Viruses closely related to HBV(“Hepadna viruses”)are known in many species other than humans.4.HBV is a major deadly infectious agent.5.Males are more likely than females to become chronic carriers of HBV and to die as a consequence of infe
3、ction.6.HBV related deaths are highest in older males;high HBV prevalence decreases the male to female ratio in older age groups.7.There are a series of polymorphisms that affect susceptibility to chronic infection.8.Parents who are carriers of HBV have a higher ratio of males to females in their ne
4、wborn offspring than do parents who have antibody against the surface antigen of HBV;high HBV incidence increases the male to female ratio at birth.9.There may be host advantages to the carrier state.10.The worldwide vaccination program is decreasing the prevalence of HBV.11.Virus sequences are very
5、 common in the human genome.12.HBV as an“engine”of human evolution.13.Were viruses an early form of life and,possibly,the earliest form?Primary Cancer of the LiverWorldwide:Third most common cause of death from cancer in males Seventh most common cause of death from cancer in females More than a mil
6、lion deaths per year Hepatitis B virus(about 85%)and hepatitis C virus account for most of these cancers Many other factors involved in the pathogenesisHuman Hepatitis VirusesGenomeVirus GenomeSize(Kb)EnvelopeClassificationHAV RNA7.5 -Picornavirus(Hepatovirus)HBV DNA3.2HBsAgHepadnavirusHCV RNA9.4 +P
7、estivirus-orFlavivirus-likeHDV RNA1.7HBsAgUnclassifiedHEV RNA7.5 -Claicivirus-likeor Alpha-likesupergroupHBV is one of the most common infections in the world.About 600,000 to 1,000,000 deaths per year are attributable to the diseases associated with HBV.(H.Margolis,Center for Disease Control.Paper
8、presented at ThirdInternational Conference on Therapies for Viral Hepatitis,Maui,12/12/99)VirusNumberInfected(Millions)Low 15%34CaseFatalityRateTotalDeaths(Millions)High 25%100%371HIVHBV3492.855.7PREDICTED DEATHS FROM PREVALENT CARRIERS OF HIV AND HBV “Hepatitis B is a viral infection of the liver.M
9、ore than two thousand million(2 billion)people alive today have been infected with the hepatitis B virus.Approximately 350 million are chronically infected and are at high risk of serious illness and death from cirrhosis of the liverand primary liver cancer.Hepatitis B is preventable with a safe and
10、 effective vaccine the first vaccine against cancer.”WHO website,20040500100015002000250025-3435-4445-5455-6465-74Age group(years)Mortality per 100,000 pyM HBV+M HBV-F HBV+F HBV-MORTALITY BY AGE,GENDER AND HBV RESPONSEHAIMEN CITY,CHINAG.Chen,W.Lin,F.Shen,U.Iloeje,T.London and A.EvansInter.J.of epid.
11、2004,in printHEPATITIS B VIRUS MORPHOLOGYCharacteristicsNucleic acid:DNAClassification:hepadnavirus type 1Serotypes:multipleIn vivo replication:reverse transcription inliver and other tissuesIn vitro propagation:primary hepatocyteculture and transfectionby cloned HBV DNA42 nm22 nmCHBsAgHBcAgHBV DNAH
12、EPATITIS B LIKE VIRUSES HepadnavirusesHumanHomo sapiensHBVGorillaGorilla sp.HBVChimpanzeePan troglodytesChHBVGibbonFamily HylobatidaeHBVOrangutanPongo pygmaeusHBVWoolly monkey Lagothrix lagotrichaWMHBVTree shrewTupaia belangeriHBV(KangarooFamily MacropodidaeKHV)Woodchuck or GroundhogMarmota monaxWHV
13、Beechey ground squirrel Spermophilus beecheyiGSHVArctic squirrelS.parryi kennicottiASHBVRichardson ground squirrel S.richardsoniiRGSHV(Tree squirrelSciurus carolinensis THBV)Pekin duck Anas domesticusDHBVGreat blue heronArdea herodiasHHBVGrey heronA.cinereaHHBV Snow gooseAnser caerulescensSGHBVRoss
14、gooseA.rossiiRGHBVWhite StorkCiconia ciconiaSTHBVDemoiselle craneAnthropoides virgo CHBVGrey crowned crane Balearica regulorumCHBV(Stink snakeElaphe carinataSSHV)(Items in parentheses have not been validated.Tree shrews were experimentally infected.)CONTROL OF HEPATITIS B VIRUS IN CHINAZ.Y.Xu,T.Q.Ya
15、n,S.J.Zhao,et al.Shanghai Medical University“Infant HBV immunization has been implemented into public health service in China since 1986 the seropositivity for HBsAg was reduced from 16.3%(879/5397)of historical controls to 1.43%(70/4886)in cross-sectional study and 1.81%(210/11582)in a cohort study
16、.”In the United States,the number of new HBV infections per year has declined from an average of 260,000 in the 1980s to about 78,000 in 2001.The highest rate of disease occurs in the 20-49 age group.Greatest decline is the consequence of the routine HBV vaccination program among children and adoles
17、cents.There are an estimated 1.25 million chronically infected Americans,of whom 20-30%acquired their infection in childhood.CDC Website,2004 HBV VACCINATION IN THE UNITED STATESA universal childhood vaccination program was undertaken between 1981 and 1983 in Native Americans in Alaska,USA(McMahon,e
18、t al.,1996).Acute hepatitis B infection dropped from 215 cases/100,000 before the vaccination program,to 7 to 14 cases in 1993 after the program was in place.In 1995,no cases were reported.HBV VACCINATION IN ALASKA,USAAs of May 2003,151(79%)of 192 national members of the WHO had universal childhood
19、vaccination programs.There are 89 member states that have been designated as having a high prevalence of HBV carriers.Sixty four(72%)have universal infant vaccination programs.It is the goal of the WHO to have vaccination programs in all countries by 2007.Hepatitis B Virus Worldwide Vaccination Prog
20、ramDistribution of Australia Antigen(HBsAg)by GenderMarshall Islands,USTTPI Male Female TotalCebu,Philippines Male Female TotalManila,Philippines Male Female TotalCashinahua,Peru Male Female TotalTotal Number24322649543033476413859197454489NumberPositive19143327103763910616PercentPositive7.86.26.76.
21、33.04.84.35.14.622.213.618.0Blumberg,et al,Amer.J.Human Genetics 18,594,1966 Parents responseTo HBVEither parent HBsAg+:anti-HBs Both parents HBsAg-:anti-HBs Both parents HBsAg-:either parent anti-HBs+Couples(No.)3329 154Live birthsMale Females60(1.8 0.2)51(1.8 0.2)24(1.6 0.1)24(0.7 0.1)35(1.2 0.2)2
22、2(1.4 0.1)Sex ratio250(161,429)*146(96,230)*109(91,131)*PLATI,GREECE.NUMBER OF MALE AND FEMALE LIVE BIRTHS ACCORDING TO THE RESPONSES TO HBV OF PARENTS*In parentheses,the 5 percent confidence limits.Blumberg,B.S.Sex differences in response to Hepatitis B Virus,Arthritis and Rheumatism,22,1261,1979He
23、patitis B and Sex Ratio:Individual Level EstimatesNotes:This table shows sex ratios among the children of carrier and non-carrier parents in four regions.Data were collected by testing married women and,in all cases except for Greenland,their husbands for HBV.Detailed reproductive histories were als
24、o collected.The table represents all births to women in those samples,with generally more than one birth to each women.The last two studies(Greece 2 and France)were designed specifically to test the hypothesis that HBV affects offspring sex ratio,and were run after the original theory was expressed.
25、LocationGreenlandGreenlandKar Kar IslandKar Kar IslandGreece 1Greece 1PhilippinesPhilippinesGreece 2Greece 2FranceFranceHBV StatusPositiveNegativePositiveNegativePositiveNegativePositiveNegativePositiveNegativePositiveNegativeSons6417463163852876630452100620149 60 1945420646255413013095512122Sex Rat
26、io1.070.901.170.791.851.131.611.011.731.051.661.22DaughtersFrom Oster,E.2004Notes:Sex ratio is number of boys for each girl.Only countries with more than 15,000 people used to caclulate HBV pravalence are included.Citations for each country are in Appendix B.Sex Ratio at BirthSEX RATIO AND HEPATITIS
27、,WORLDHepatitis Rate(%)BrazilBelarusBangladeshIranMalaysiaSingaporeIsraelPakistanChinaMexicoTurkeyFranceIrelandGreeceSouth KoreaSpainAustraliaItalyPolandJapan1.141.121.11.081.061.041.0210246810121416Oster,E.,Hepatitis B and the Case of the Missing Women,Presentation,October 12,2004N.Amer&W.EuropeEFF
28、ECTS OF VACCINATION PROGRAMALASKA High HBV prevalence among Alaskan Native Americans;low among non-Native American Universal vaccination program(including catch-up)instituted in early 1980s.Oster,E.,Hepatitis B and the Case of the Missing Women,Presentation,October 12,20041996-20021991-19951986-1990
29、1980-1985CHANGES IN SEX RATIO IN ALASKA BEFORE AND DURING VACCINATION PROGRAM1.161.141.121.11.081.061.041.021Native American High HBVNative American Low HBVNon-Native AmericanOster,E.,Hepatitis B and the Case of the Missing Women,Presentation,October 12,2004 HBV explains about 50%of the missing wome
30、n overall:over 90%in China,11%in India Vaccination programs appear to decrease sex ratioOster,E.,Hepatitis B and the Case of the Missing Women,Presentation,October 12,2004Microorganism Gene Affinity ClustersLocusAlleleAgent/DiseaseChromFunctionMHC Class IIDRB1*1302HBV chronicity(P)Chrom 6Immune resp
31、onseHBV response to interferonMalaria,cerebral(P)Pappiloma virusVDRttHBV chronicity(P)Chrom 12Vitamin D ReceptorBinds Vit.D 1,25D3ttTB Pulmonary(P)TTLeprosy,tuberculoid(P)TtLeprosy,infection(P)ttLeprosy,lepromatous(P)ttBone mineral density,lower Osteoporosis,increase risk Prostaticcancer(P)Inflamato
32、ry boweldiseaseMicroorganism Gene Affinity Clusters(cont.)LocusAlleleAgent/DiseaseChromFunctionTNFG-308HBV chronicityChrom 6Tumor NecrosisFactorMalaria,cerebralMicrocutaneous leish.Lepromatous leprosyMeningococcalMeningitisTrachomaAsthmaMBPCodon 52HBV chromicityChrom 10Mannose BindingProteinSLE,HIV(
33、?)Infections in childhoodSM-1 5q31-33SchistosomiasisChrom 5Schist.Susceptibility?HBV chronicityIL-10 PromoterMutat.-108HBV chronicityChrom 1Immune responseMutat.-059HBV chronicityHBV and Iron in Downs Syndrome Patients With and Without HBsAgIncreased Hemoglobin,Hematocrit,Serum Iron and decreased To
34、tal Iron Binding Capacity(TIBC)in 20 Downs Syndrome patients with serum HBsAg compared to 20 without.The differences are significant.HBsAg(+)MeanSDHBsAg(+)MeanSDHemoglobing/100ml15.21.414.91.4Hematocrit%44.23.843.53.6Serum Ironmg/100ml163.7115.184.133.6TIBCmg/100ml250.4108.2356.8144.8Sutnick,Blumber
35、g,Lustbader.Ann.Int.Med.81,855,1974Serum Iron Levels(mg/dl)Serum Iron levels in 1)Patients with Downs Syndrome 2)Patients on renal dialysis and 3)Residents of a rural community in Senegal,West Africa.Blumberg in Szentivanyi and Friedman,Editors,Viruses,Immunity and Immunodeficiency,Plenum 1986HBsAg(
36、+)HBsAg(-)NumberDowns SyndromeMaleFemale164 -84 -40 -Total164 84 40Renal Dialysis MaleFemale 114 214 98 100 40 117 Total 145 100 220 Senegal Male Female 77 81 75 58 81 112 Total 79 65 193Large numbers of retroviral sequences(includingthose of HBV)are found in the human genome.These are often the“fos
37、sil”record of viruses that were incorporated into the germ line in previous generations.It is estimated that 8%of the modern human genome is made of retroviral sequences,a larger number than the coding sequences,and they are often highly conserved.Modified from Blumberg,B.S.2005,Hepatitis B virus.Co
38、njectures on human interactions and the origin of life,in,“Life As We Know It”,Volume 10 of the series“Cellular Origins,Life in Extreme Habitats and Astrobiology”edited by J.Seckbach,Springer,Dordrecht,NL.;and Kilbourne,E.D.(2004).Virus paleontology,disease,and evolution:an introduction.Proc.Amer.Ph
39、ilosophical Society 148:261 and following articles.Hepatitis B vaccination is one of the largest worldwide disease prevention programs.It has decreased the spread of HBV,particularly in China and East Asia.It has significantly decreased morbidity from liver disease and prevented the death of million
40、s.HBV vaccination appears to prevent primary cancer of the liver;it is the first widely used preventive cancer vaccine.SUMMARY(1)There are important non-pathological interactions of HBV with Humans.Parents who are carriers of HBV have a higher ratio of males to females among their offspring than par
41、ents who developed antibody against the surface antigen.This may account for the high sex ratios seen in China and in other areas with a high prevalence of HBV infection.The apparent“loss”of females in these populations may be ascribed,at least in part,to HBV infection.In two studied populations the
42、 HBV vaccination has decreased the ratio of males to females among newborns.If confirmed,this may have important,biological,demographic and economic effects.SUMMARY(2)The response of the host to HBV infection is related to a series of polymorphic locii that are,in turn,related to other disease causing agents.There may be advantages to the HBV carrier state at certain periods of the hosts life,i.e.there is increased iron retention in HBV carriers compared to those with anti-HBs and uninfected people.HBV is integrated into the genomes of tens of millions of humans.SUMMARY(3)
